The vascular system, responsible for the transport of nutrients, oxygen, and waste removal, overcomes the limitations of oxygen diffusion in solid tissues through blood perfusion, thereby preventing necrosis. The mechanical stimuli from blood flow are pivotal for vascular development and engineering, influencing endothelial cell morphology and vessel remodeling via mechanosensing. Current organ-on-chip systems, while successful in applying dynamic flow to endothelial cells, have limitations, including dependency on pumps and confinement to closed microfluidic channels. Additionally, the interaction between immune cells and these systems under long-term recirculating flow conditions has not been adequately demonstrated.
This thesis introduces a novel biofabrication and device manufacturing technique that utilizes a flexible, patternable sacrificial material on a 2D surface. This material morphs in response to an aqueous hydrogel and then degrades, forming perfusable vascular networks within a natural hydrogel matrix. We achieved perfusion using a rocker mechanism that periodically changes tilt direction, while the open-well design facilitates the visualization of perfusable tubular tissues via clinical ultrasound imaging and the construction of complex, vascularized hepatic tissues embedded in gel matrices (Chapter 2). To mimic the unidirectional recirculating flow characteristic of blood vessels, we created the UniPlate platform, combining injection molding with 3D printing (Chapter 3). This innovation allows for the perfusion and recirculation of monocytes through vascular channels without compromising cell viability or eliciting an inflammatory response. Furthermore, by integrating cancer spheroids into the vascular tissues on UniPlate, we developed a vascularized cancer spheroid model that exhibited temporally dependent and tissue-specific macrophage recruitment toward tumor sites with continuous monocyte recirculation (Chapter 4). Collectively, this series of research work introduces a versatile and robust platform capable of replicating vascular functions and immune responses, offering a substantial advancement in the investigation of vascular biology and the mechanism of disease progression. / Thesis / Doctor of Philosophy (PhD) / Vascular networks of the circulatory system are crucial organs in the body, determining the life and death of tissues and organisms by distributing nutrients and oxygen throughout the body. Dysfunction in blood vessel systems is closely related to clinical diseases such as stroke, atherosclerosis, tumor angiogenesis, and cancer metastasis. Mechanical stimuli in blood vessels play a crucial role in regulating the structure and function of endothelial cells during in vivo embryonic development and in vitro vascular tissue formation. Understanding and mimicking the complex environment of blood vessels is vital for studying diseases related to endothelial dysfunction. In this thesis, we introduce a novel subtractive manufacturing method to create three-dimensional (3D) perfusable tubular tissues within a hydrogel. Unidirectional recirculating flow, stromal cells and spheroids, as well as circulating immune cells, were then introduced to the engineered vascular tissues to develop more complex tissue models. These models reproduce the cell diversity, 3D structure, mechanical stimuli, and immune components found in the native tissue microenvironment, providing a valuable tool for the study of vascular diseases and the development of potential treatments.
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/29647 |
| Date | January 2024 |
| Creators | Zhang, Feng |
| Contributors | Zhang, Boyang, Biomedical Engineering |
| Source Sets | McMaster University |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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